Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Nat Commun. 2023 Mar 31;14(1):1816. doi: 10.1038/s41467-023-37452-6.
Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol enhances the ability of the anthelmintic Ivermectin to paralyze C. elegans and the ruminant nematode parasite Haemonchus contortus. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through a validated anthelmintic target.
人类和家畜的线虫寄生虫对人类健康、经济发展和粮食安全构成重大负担。家畜寄生虫的驱虫药耐药性普遍存在，许多人类的线虫寄生虫缺乏有效治疗方法。在这里，我们提出了一个硝苯基哌嗪支架，它能在模式线虫秀丽隐杆线虫中迅速引起运动缺陷。我们称这个支架为 Nemacol，并表明它抑制囊泡乙酰胆碱转运体（VAChT），这是商业动物和作物健康组织认可的一种可行的驱虫靶点。我们证明，有可能创造出 Nemacol 类似物，在保持体内活性的同时，将其对哺乳动物 VAChT 的亲和力降低 10 倍。我们还表明，Nemacol 增强了驱虫药伊维菌素麻痹秀丽隐杆线虫和反刍动物线虫寄生虫捻转血矛线虫的能力。因此，Nemacol 代表了一种有前途的新驱虫支架，它通过一个经过验证的驱虫靶点发挥作用。
